Cell therapy is a potentially curative therapy against tumors, viruses and bacterial pathogens. Cell therapy can also be used to treat autoimmune diseases (e.g. rheumatoid arthritis, multiple sclerosis and type I diabetes), neurological disorders (such as Alzheimer's, ALS and Parkinson's disease), as well as anti-aging treatment, wound healing and treatment of cardiovascular disorders. Harnessing the power of the immune system to treat or prevent diseases is a major goal of immunotherapy. A variety of immunotherapy methods and compositions have been developed in order to enhance or suppress the immune response in patients. Cell therapy methods often involve ex-vivo manipulations such as proliferation, differentiation and/or activation of cells. Cells that are more than minimally manipulated are considered to be biological drugs by the United States Food and Drug Administration (USFDA) as well as regulatory agencies in other jurisdictions. Before such biological drugs can be marketed for treatment or prevention of any disease, these products must first be investigated in human clinical trials under an Investigational New Drug Application (IND) or equivalent.
For commercial use, the processes used to manufacture biological drugs containing living cells must be standardized so that the resulting cells have pre-determined identity, functional and viability release criteria. The processes to cause the proliferation, differentiation and/or activation of cells intended for use as a biological drug generally occurs ex-vivo where the cells are kept in nutrient-rich culture media. However, prior to administering the cells to humans, the cells must be transferred to a non-nutrient infusion buffer. Because these buffer solutions do not contain nutrients, the cells remain viable for only short periods of time. Further, even if the cells remain viable after being placed in non-nutrient infusion buffer, they quickly lose their unique identity and functional characteristics. Losing their unique identity and functional characteristics disqualifies the cells to be used as a biological drug. This limitation requires that cells intended for use of biological drugs must be formulated at or near the point-of-care. The requirement that cells be formulated at or near the point-of-care because of the limited shelf life of living cell products in formulation severely limits the commercial viability of this class of product.
Living cells are relatively stable in nutrient rich culture media. Examples of nutrient-rich culture media include, for example, X-Vivol 5 (BioWhittaker, Walkersville, Md.), RPMI 1640, DMEM, Ham's F12, McCoys 7A and Medium 199. The medium can be supplemented with additional ingredients including serum, serum proteins, growth suppressing, and growth promoting substances, such as mitogenic monoclonal antibodies and selective agents for selecting genetically engineered or modified cells. However, transfer of the cells to non-nutritive buffer such as is required for administration to a patient can lead to rapid degradation of the cellular identity, cell viability and the functional characteristics of the cells. Examples of non-nutrient buffers include, for example, isotonic solutions such as normal saline, phosphate buffered saline, 5% dextrose, Plasma-Lyte (Baxter Scientific, Deerfield, Ill.) and Normasol (Abbott Laboratories, Abbott Park, Ill.). In addition, when cells are transferred to non-nutritive buffer, it is generally believed that reagents that provide activation and/or differentiation signals as well as other components such as stimulatory molecules or cytokines should be removed prior to transfer into non-nutritive buffer. (See U.S. Pat. No. 6,867,041 to Berenson et al.) Therefore, cells in non-nutritive buffer generally have a limited shelf-life and can, for example, start losing their identifying properties and activity within minutes and rarely maintain their functional and identity characteristics for more than a few hours.
Currently, immunotherapeutic compositions that include living cells are generally produced in a cGMP facility close to the point of care of the patient (See US patent Publication no. 2003/0175242 to Gruenberg). Formulation of biological drugs with living cells must be performed under highly controlled and sterile conditions in cGMP facilities. The live cells are manipulated at the cGMP facility and formulated for infusion into a patient. Once the cells are prepared for infusion, the cells are quickly transferred to the point of care site and administered to the patient. The major drawback of this process is that cGMP facilities need to be present near every point of care site. The cGMP facilities require considerable monetary capital to staff and run under the required rules and regulations. The need to establish a multiplicity of these centers at or near every point of care is cost prohibitive and a severe limitation to the commercial potential of this class of drug. This leads to a difficult choice of incurring great expense by building a large number of cGMP facilities in order to increase accessibility to patients or to providing limited accessibility for patients by building only a limited number of cGMP facilities to minimize the capital expenditures. Thus, there is a need in the field of live cell therapeutics for methods that enable cells in non-nutritive buffer to have a more extended shelf-life. Furthermore, a method is needed that would enable the packaging, shipping and mass distribution of formulated cell products suspended in non-nutrient containing infusion buffer.
Problems with maintaining the identity and function of cells used in adoptive immunotherapy after formulation are described, for example, in U.S. Patent Publication No. 2003/0175272 to Gruenberg. This publication teaches that T-cells must be reactivated just prior to patient administration (no more than 4 hours prior to infusion) to maintain functional characteristics of cytokine production. The function of the cells can be maintained up to 48 hours only if the formulation includes autologous plasma. However, collection of plasma from every intended patient is not conducive to mass distribution and commercialization.